The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
The human immune system may generally be divided into two arms, referred to as “innate immunity” and “adaptive immunity.” The innate arm of the immune system is predominantly responsible for an initial inflammatory response via a number of soluble factors, including the complement system and the chemokine/cytokine system; and a number of specialized cell types including mast cells, macrophages, dendritic cells (DCs), and natural killer cells. In contrast, the adaptive immune arm involves a delayed and a longer lasting antibody response together with CD8+ and CD4+ T cell responses that play a critical role in immunological memory against an antigen. A third arm of the immune system may be identified as involving γδ T cells and T cells with limited T cell receptor repertoires such as NKT cells and MAIT cells.
For an effective immune response to an antigen, antigen presenting cells (APCs) must process and display the antigen in a proper MHC context to a T cell, which then will result in either T cell stimulation of cytotoxic and helper T cells. Following antigen presentation successful interaction of co-stimulatory molecules on both APCs and T cells must occur or activation will be aborted. GM-CSF and IL-12 serve as effective pro-inflammatory molecules in many tumor models. For example, GM-CSF induces myeloid precursor cells to proliferate and differentiate into dendritic cells (DCs) although additional signals are necessary to activate their maturation to effective antigen-presenting cells necessary for activation of T cells. Barriers to effective immune therapies include tolerance to the targeted antigen that can limit induction of cytotoxic CD8 T cells of appropriate magnitude and function, poor trafficking of the generated T cells to sites of malignant cells, and poor persistence of the induced T cell response.
DCs that phagocytose tumor-cell debris process the material for major histocompatibility complex (MHC) presentation, upregulate expression of costimulatory molecules, and migrate to regional lymph nodes to stimulate tumor-specific lymphocytes. This pathway results in the proliferation and activation of CD4+ and CD8+ T cells that react to tumor-associated antigens. Indeed, such cells can be detected frequently in the blood, lymphoid tissues, and malignant lesions of patients.
New insights into the mechanisms underlying immune-evasion, together with combination treatment regimens that potentiate the potency of therapeutic vaccination—either directly or indirectly—through combination with immune checkpoint inhibitors or other therapies, have served as a basis for the development of vaccines that induce effective antitumor immunity.
Tumor cells genetically modified to secrete GM-CSF have been used in various strategies in an effort to generate an effective immune response to tumors, however systemic cytokine administration has not induced a direct anti-cancer response in randomized controlled trials. Irradiated GM-CSF-secreting tumor cells injected subcutaneously into patients have been shown to stimulate a local response comprising DCs, macrophages, and granulocytes. The accumulation of large numbers of APCs suggests that one function of GM-CSF in this model involved the augmentation of tumor antigen presentation. Moreover, tumor cell vaccines have shown to be safe in patients. However, the clinical efficacy of this approach has been yet to be proven.
In the context of infection, Toll-like receptor (“TLR”) agonists have been shown to render dendritic cell activation immunogenic, whereas lack of TLR signaling can lead to tolerance. The implication from these studies is that localized TLR stimulation might enhance antitumor response when given as part of a combinatorial vaccine. WO2011139769 describes the formulation and use of a combined GM-CSF-secreting tumor cell (GVAX) vaccine, together with TLR4 stimulation, which reportedly provided anti-tumor efficacy in several murine models. Its efficacy in humans remains, however, to be proven.
There remains a need for improved compositions and methods for immunologic strategies to treating diseases such as cancer that can be refractory to traditional therapeutic approaches.